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Use of gene expression profiling to identify candidate genes for pretherapeutic patient classification in acute appendicitis.

ABSTRACT: Phlegmonous and gangrenous appendicitis represent independent pathophysiological entities with different clinical courses ranging from spontaneous resolution to septic disease. However, reliable predictive methods for these clinical phenotypes have not yet been established. In an attempt to provide pathophysiological insights into the matter, a genomewide gene expression analysis was undertaken in patients with acute appendicitis. Peripheral blood mononuclear cells were isolated and, after histological confirmation of PA or GA, analysed for genomewide gene expression profiling using RNA microarray technology and subsequent pathway analysis. Samples from 29 patients aged 7-17 years were included. Genomewide gene expression analysis was performed on 13 samples of phlegmonous and 16 of gangrenous appendicitis. From a total of 56 666 genes, 3594 were significantly differently expressed. Distinct interaction between T and B cells in the phlegmonous appendicitis group was suggested by overexpression of T cell receptor α and β subunits, CD2, CD3, MHC II, CD40L, and the B cell markers CD72 and CD79, indicating an antiviral mechanism. In the gangrenous appendicitis group, expression of genes delineating antibacterial mechanisms was found. These results provide evidence for different and independent gene expression in phlegmonous and gangrenous appendicitis in general, but also suggest distinct immunological patterns for the respective entities. In particular, the findings are compatible with previous evidence of spontaneous resolution in phlegmonous and progressive disease in gangrenous appendicitis.

SUBMITTER: Kiss N

PROVIDER: S-EPMC7893459 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAcute appendicitis (AA) (OMIM: 107700) is an inflammatory disease which is characterized by appendiceal inflammation. Genetic and environmental factors contribute to the development of AA. Especially, multiple genetic factors appear to be promising in the explanation of etiopathogenesis of AA. IL-6 (Interleukin-6) is an inflammatory cytokine and IL-6 receptor (IL-6R) plays an important role in the immune response. IL-6 (-572G/C rs1800796) and IL-6R (1:G.154448302 T > C rs7529229) gene polymorphisms may have an impact on cytokine production, immune response and these gene polymorphisms may be used as inflammatory markers in the diagnosis of appendicitis.MethodA total of 75 children with appendicitis, and 75 healthy children were included in the study. DNA extracts were obtained from peripheral lymphocytes. Single-nucleotide polymorphisms (SNPs) were analysed using an automated SYBR® Green RT-PCR system in pediatric patients with appendicitis (n = 75) and healthy controls (n = 75).ResultsThe allele and genotype frequencies for IL-6 rs1800796 and IL-6R rs7529229 polymorphisms were not different between the study groups (p > 0.05). Any statistically significant differences as for age, sex and other laboratory factors were not detected between the patients with appendicitis for genotype-allele frequencies (p > 0.05). Still in analyses performed to determine correlations among age, and gender of the patients, routine laboratory parameters and allele-genotype frequencies, a statistically significant intergroup difference was not detected. Genotype and allele frequencies were consistent with Hardy-Weinberg equilibrium (HWE) in all groups.DiscussionThis is the first study to investigate the effects of functional two polymorphisms on IL-6 and IL-6R genes in a pediatric patient group with AA risk. With this study we investigated the contribution of IL-6 (-572G/C rs1800796) and IL-6R (1:G.154448302 T > C rs7529229) polymorphisms on pathogenesis, and severity of AA in pediatric patients with AA: These results will guide further genetic researches to be performed on the role of IL-6 and IL-6R in AA.ConclusionsGiven the putative biological importance of this SNPs, these emerging data can provide a new foundation to stimulate future debate and genetic investigations of AA, focusing on new molecular mechanisms such as other IL gene polymorphisms, particularly in accessible peripheral tissues for novel molecular diagnostics for appendicitis.

Project description:Importance:Studies have compared surgical with nonsurgical therapy for acute uncomplicated appendicitis, but none of these studies have a patient-centered perspective. Objectives:To evaluate how patients might choose between surgical and nonsurgical therapy for acute uncomplicated appendicitis and to identify targets to make antibiotic treatment more appealing. Design, Setting, and Participants:This study comprised an online survey and an in-person sensitivity analysis survey. For the web survey, a convenience sample of 1728 respondents were asked to imagine that they or their child had acute uncomplicated appendicitis, provided information about laparoscopic and open appendectomy and antibiotic treatment alone, and asked which treatment they might choose. The web survey was open from April 17, 2016, through June 16, 2016, and was disseminated via email link, a poster with a Quick Response code, and social media. For the sensitivity analysis, 220 respondents were given the same scenario and options. Those who chose surgery were asked whether certain factors influenced their decision; each factor was incrementally improved during questioning about whether respondents would consider switching to antibiotics. These participants were recruited at public venues from June 3, 2016, to July 31, 2016. Web survey data were analyzed from June 17, 2016, to September 21, 2017. Sensitivity analysis data were analyzed from August 1, 2016, to September 21, 2017. Main Outcomes and Measures:Treatment preferences. Results:Among the 1728 web survey respondents, 1225 (70.9%) were female and 500 (28.9%) were male (3 [0.2%] either did not answer or responded as "gender fluid" within the comments section of the survey), and most self-reported being between 50 and 59 years of age (391 [22.6%]) and being non-Hispanic white (1563 [90.5%]). For themselves, 1482 respondents (85.8%) chose laparoscopic appendectomy, 84 (4.9%) chose open appendectomy, and 162 (9.4%) chose antibiotics alone. For their child, 1372 respondents (79.4%) chose laparoscopic appendectomy, 106 (6.1%) open appendectomy, and 250 (14.5%) antibiotics alone. Respondents were somewhat more likely to choose antibiotics for themselves if they had education beyond college (105 [12.6%]; P?<?.001), identified as other than non-Hispanic white (24 [14.9%]; P?<?.001), or did not know anyone who had previously been hospitalized (12 [15.8%]; P?=?.02), but they were less likely to choose antibiotics if they were surgeons (11 [5.4%]; P?=?.008). Of the 220 participants interviewed for the sensitivity analysis, 120 (54.5%) were female and 100 (45.5%) were male, and most self-reported being between 18 and 24 years of age (53 [24.1%]) and being non-Hispanic white (204 [92.7%]). Their responses suggested that improvements in the short- and long-term failure rate of antibiotic treatment-rather than reductions in the duration of hospitalization or antibiotic treatment-were more likely to increase the desirability of choosing antibiotics. Conclusions and Relevance:Most patients may choose surgical intervention over antibiotics alone in treatment of acute uncomplicated appendicitis, but a meaningful number may choose nonoperative management. Therefore, from a patient-centered perspective, this option should be discussed with patients, and future research could be directed at reducing the failure and recurrence rates of antibiotic treatment for appendicitis.

Project description:Acute appendicitis is one of the major causes for emergency surgery in childhood and adolescence. Appendectomy is still the therapy of choice, but conservative strategies are increasingly being studied for uncomplicated inflammation. Diagnosis of acute appendicitis remains challenging, especially due to the frequently unspecific clinical picture. Inflammatory blood markers and imaging methods like ultrasound are limited as they have to be interpreted by experts and still do not offer sufficient diagnostic certainty. This study presents a method for automatic diagnosis of appendicitis as well as the differentiation between complicated and uncomplicated inflammation using values/parameters which are routinely and unbiasedly obtained for each patient with suspected appendicitis. We analyzed full blood counts, c-reactive protein (CRP) and appendiceal diameters in ultrasound investigations corresponding to children and adolescents aged 0-17 years from a hospital based population in Berlin, Germany. A total of 590 patients (473 patients with appendicitis in histopathology and 117 with negative histopathological findings) were analyzed retrospectively with modern algorithms from machine learning (ML) and artificial intelligence (AI). The discovery of informative parameters (biomarker signatures) and training of the classification model were done with a maximum of 35% of the patients. The remaining minimum 65% of patients were used for validation. At clinical relevant cut-off points the accuracy of the biomarker signature for diagnosis of appendicitis was 90% (93% sensitivity, 67% specificity), while the accuracy to correctly identify complicated inflammation was 51% (95% sensitivity, 33% specificity) on validation data. Such a test would be capable to prevent two out of three patients without appendicitis from useless surgery as well as one out of three patients with uncomplicated appendicitis. The presented method has the potential to change today's therapeutic approach for appendicitis and demonstrates the capability of algorithms from AI and ML to significantly improve diagnostics even based on routine diagnostic parameters.

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Use of gene expression profiling to identify candidate genes for pretherapeutic patient classification in acute appendicitis.

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